Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses
Authors: Eleni Sofianopoulou, Stephen K Kaptoge, Shoaib Afzal, Tao Jiang, Dipender Gill, Thomas E Gundersen, Thomas R Bolton, Elias Allara, Matthew G Arnold, Amy M Mason, Ryan Chung, Lisa A M Pennells, Fanchao Shi, Luanluan Sun, Peter Willeit, Nita G Forouhi, Claudia Langenberg, Stephen J Sharp, Salvatore Panico, Gunnar Engström, Olle Melander, Tammy Y N Tong, Aurora Perez-Cornago, Margareta Norberg, Ingegerd Johansson, Verena Katzke, Bernard Srour, María José Sánchez, Daniel Redondo-Sánchez, Anja Olsen, Christina C Dahm, Kim Overvad, Magritt Brustad, Guri Skeie, Conchi Moreno-Iribas, N Charlotte Onland-Moret, Yvonne T van der Schouw, Konstantinos K Tsilidis, Alicia K Heath, Claudia Agnoli, Vittorio Krogh, Ian H de Boer, Camilla Jannie Kobylecki, Yunus Çolak, Armin Zittermann, Johan Sundström, Paul Welsh, Elisabete Weiderpass, Elom K Aglago, Pietro Ferrari, Robert Clarke, Marie-Christine Boutron, Gianluca Severi, Conor MacDonald, Rui Providencia, Giovanna Masala, Raul Zamora Ros, Jolanda Boer, Wm Monique Verschuren, Peggy Cawthon, Louise L Schierbeck, Cyrus Cooper, Matthias B Schulze, Manuela M Bergmann, Anke Hannemann, Stefan Kiechl, Hermann Brenner, Natasja M van Schoor, Juan R Albertorio, Carlotta Sacerdote, Allan Linneberg, LineL Kårhus, José María Huerta, Liher Imaz, Christel Joergensen, Yoav Ben-Shlomo, Annamari Lundqvist, John Gallacher, Naveed Sattar, Angela M Wood, Nicholas J Wareham, Børge G Nordestgaard, Emanuele Di Angelantonio, John Danesh, Adam S Butterworth, Stephen Burgess
Journal: The Lancet Diabetes & Endocrinology (2023)

BackgroundRandomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks.MethodsObservational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality.FindingsObservational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically predicted 25(OH)D with coronary heart disease (odds ratio [OR] per 10 nmol/L higher genetically-predicted 25(OH)D concentration 0·98, 95% CI 0·95–1·01), stroke (1·01, [0·97–1·05]), or all-cause mortality (0·99, 0·95–1·02). Null findings were also observed in genetic analyses for cause-specific mortality outcomes, and in stratified genetic analyses for all outcomes at all observed levels of 25(OH)D concentrations.InterpretationStratified Mendelian randomisation analyses suggest a lack of causal relationship for 25(OH)D concentrations with both cardiovascular and mortality outcomes for individuals at all levels of 25(OH)D. Our findings suggest that substantial reductions in mortality and cardiovascular morbidity due to long-term low-dose vitamin D supplementation are unlikely even if targeted at individuals with low vitamin D status.FundingBritish Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer.